Aldosterone Synthase Inhibitors for Cardiorenal Protection: Ready for Prime Time?

Abstract

Background: Aldosterone is the principal mineralocorticoid hormone and the final effector of the renin-angiotensin-aldosterone system. This hormone is primarily synthesized by the CYP11B2 enzyme and produced by the adrenal zona glomerulosa. Through genomic and non-genomic effects, it plays an important role in cardiovascular and renal disease. To counteract aldosterone-mediated damage, steroidal mineralocorticoid receptor antagonists are recommended by international guidelines, but endocrine side effects often limit their use in a substantial proportion of patients. Conversely, nonsteroidal mineralocorticoid receptor antagonists, with an improved selectivity and safety profile, are gaining a prominent position among therapeutic pillars. However, blocking the mineralocorticoid receptors does not completely inhibit aldosterone effects because of escape mechanisms and non-genomic activity. Thus, inhibiting aldosterone synthesis could be a promising strategy to prevent aldosterone-mediated cardiorenal damage. The limited specificity for CYP11B2 and side effects due to off-target activity hampered the development of first-generation aldosterone synthase inhibitors (ASIs).

Summary: The development of highly specific ASIs led to successful clinical trials in patients with resistant and uncontrolled hypertension. Additionally, a recent randomized clinical trial showed a significant benefit of ASIs in patients with chronic kidney disease and albuminuria.

Key messages: The strength of the clinical evidence collected so far is still limited, and larger outcome-based clinical trials are needed to confirm the promising role of ASIs in cardiorenal damage.

Keywords: Aldosterone; Aldosterone synthase inhibitors; Chronic kidney disease; Hypertension; Mineralocorticoid receptor; Mineralocorticoid receptor antagonists.

Fig. 1.

Genomic and non-genomic pathways of aldosterone signaling in epithelial and non-epithelial cells. The blue ligands marked with “A” represent aldosterone, and the purple ligands marked with “C” represent cortisol. The plasma membrane G protein-coupled receptor with seven transmembrane domains represents GPR30, the main possible receptor behind the non-genomic pathway of aldosterone. MR, mineralocorticoid receptor; GR, glucocorticoid receptor; 11βHSD2, 11β-hydroxysteroid dehydrogenase; CN, cortisone.

Fig. 2.

Mechanisms of action of aldosterone synthase inhibitors (ASIs) and steroidal or nonsteroidal mineralocorticoid receptor antagonists (S-MRAs, NS-MRAs) against the organ damage aldosterone-mediated.